K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways
| Autor: | Carsten Schaepers, Roman K. Thomas, Martin L. Sos, Jürgen Wolf, Imke Sauerland, Lars Hagmeyer, Reinhard Büttner, Karl-Otto Kambartel, Rebecca Hein, Lucia Nogova, Joachim Lorenz, Diana S.Y. Abdulla, Leonie Gogl, Martin Peifer, Nima Abedpour, Christian Grohé, Martin Hellmich, Johannes Brägelmann, Sophia Koleczko, Sabine Merkelbach-Bruse, Sebastian Michels, Merle Schüller, Ulrich Gerigk, Helen Pasternack, Matthias Scheffler, Rieke Fischer, Michaela Angelika Ihle, Monika Serke, Winfried Randerath, Jana Fassunke, Alessandra Holzem, Britta Kaminsky, Andreas H. Scheel, Anna Kron, Yon-Dschun Ko, Frank Ueckeroth, Wolfgang Schulte, Rieke Frank, Richard F. Riedel, Janna Siemanowski, Carina Heydt, Anna Eisert |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Adult Male Lung Neoplasms STK11 medicine.disease_cause Receptor tyrosine kinase Proto-Oncogene Proteins p21(ras) 03 medical and health sciences 0302 clinical medicine Carcinoma Non-Small-Cell Lung Medicine Humans neoplasms Gene Aged Aged 80 and over Mutation biology medicine.diagnostic_test business.industry Kinase Genetic heterogeneity Middle Aged 030104 developmental biology Oncology 030220 oncology & carcinogenesis biology.protein Cancer research Female KRAS business Fluorescence in situ hybridization |
| Zdroj: | Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 14(4) |
| ISSN: | 1556-1380 |
| Popis: | Introduction Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related co-mutations and their correlation with different KRAS mutation subtypes. Methods Diagnostic samples from 4507 patients with NSCLC were analyzed by next-generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next-generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing was performed in two patients. Results We identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole-exome sequencing of two patients with co-occurring phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds. Conclusion KRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS-mutated NSCLC and for future trial design. |
| Databáze: | OpenAIRE |
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